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Botanicals inhibit castrate‐resistant prostate cancer via mechanisms involving AMPK, inhibition of lipogenesis, mTOR‐mediated proliferation, and histone modification
Author(s) -
Zhao Yi,
Whelan Jay
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.371.7
Subject(s) - ampk , lipogenesis , lncap , pi3k/akt/mtor pathway , chemistry , p70 s6 kinase 1 , atp citrate lyase , acetyl coa carboxylase , protein kinase a , lipid metabolism , mtorc1 , histone , cell growth , cancer research , prostate cancer , microbiology and biotechnology , kinase , biology , signal transduction , medicine , biochemistry , pyruvate carboxylase , cancer , citrate synthase , enzyme , gene
Reprogramming of metabolic pathways and abnormal acetylation of DNA are two common features of cancer cells, including prostate cancer (PCa). Our results show that polyherbal mixtures of botanicals, like Zyflamend®, can modify lipogenesis in CWR22Rv1 cells (a castrate‐resistant human PCa cell line) by enhancing the activity of 5'adenosine monophosphate (AMP)‐ activated protein kinase (AMPK), a potential tumor suppressor protein that functions as a central energy sensor within the cell. By increasing the phosphorylation of AMPK, Zyflamend® decreases de novo lipid biosynthesis by decreasing the activity of acetyl‐CoA carboxylase (ACC) and the expression of FASN and SREBP1c. Also via AMPK, Zyflamend® inhibits the activity of mTORC1 complex by directly phosphorylating Raptor, decreasing the activity of P70 (S6K, the marker for protein synthesis). All of these effects can be mimicked by treatment of AICAR (activator of AMPK). Furthermore, Zyflamend® increases the acetylation of DNA via mechanisms that appear to involve ATP‐citrate lyase (ACLY). Thus, our results suggest that botanicals, via AMPK, inhibit castrate‐resistant prostate cancer via mechanisms that involve lipid metabolism that may reshuttle acetyl CoAs for histone acetylation, and inhibition of mTOR mediated cell proliferation. Grant Funding Source : This research was supported in part by Tennessee Agricultural Experiment Station